The impact of 3,4-methylendioxymetamphetamine (MDMA) abstinence on seeking behavior and the expression of the D2-like and mGlu5 receptors in the rat brain using saturation binding analyses.

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2-like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2-like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2-like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2-like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.

Pelvic movements during walking throughout gestation - the relationship between morphology and kinematic parameters.

BACKGROUND: Many researchers emphasize adaptations following pregnancy. Our purpose was to get more insight into how morphology interacts with the pelvic walking pattern - the segment most prone to the adaptation following altered body demands. METHODS: Thirty women were enrolled. Three experimental sessions were arranged according to the same protocol in the first, second and third trimesters of pregnancy. First, the anthropometric measures were taken, then walking trials at a self-selected speed were registered. At the end of the experimental session the subjects were asked to fill out a questionnaire on pain. FINDINGS: The sagittal plane pelvic range of motion (RoM) significantly increased throughout pregnancy. There were significant positive correlations between pelvic anthropometric dimensions and pelvic tilt and rotation primarily in the third trimester of pregnancy. Significant positive correlations were found between pelvic RoM and thigh circumference. Indicators associated with body mass increase were positively correlated with pelvic obliquity in the second trimester and pelvic tilt and rotation in late pregnancy. It is also worth noting that the individual differences were not related to back pain and that the reported correlations were observed in some but not in all trimesters. INTERPRETATION: Morphological changes following the fetus growth induced increased pelvic tilt and rotation, however, pelvis movements were not associated with back pain. Overall, the results highlight correlations between morphology and pelvis kinematic patterns in some but not in all trimesters.

Progressive changes in walking kinematics throughout pregnancy-A follow up study.

BACKGROUND: Progressive weight gain and changes in its distribution following pregnancy may be challenging for the gravidas' ability to move in a stable way. RESEARCH QUESTION: How is gait kinematics changing throughout pregnancy and to what extend is it affected by physical activity level and energy balance? METHODS: 30 women were enrolled. Three experimental sessions were arranged according to the same protocol in the first, second and third trimesters of pregnancy. Walking kinematics at a self-selected speed was registered. The total physical activity (TPA) was assessed from the subjects' questionnaires. Energy balance ('positive', 'balanced' or 'negative') was estimated as the difference between dietary energy intake and energy expenditure during 7 days. RESULTS: No significant differences were found in the spatiotemporal variables between experimental sessions. However, the gait analysis revealed significant increments in the single support and base of support (BoS) measures. Generally, the sagittal plane mobility of the lower limb joints did not differ, however, the pelvic tilt increased in late pregnancy. The hip and pelvis angles were significantly different over the gait cycle throughout gestation. The 'balanced' energy was dominant in the first trimester although the relative number of participants with negative balance increased over pregnancy. Overall, gait parameters were independent of the energy balance. However, significant correlation was found between gait parameters, such as BoS, velocity, stride length, and TPA in the advanced pregnancy. SIGNIFICANCE: The longitudinal assessment of walking kinematics demonstrates few changes adopted to accommodate for pregnancy. The enlargement of BoS is considered as a strategy to provide safety and stability. The increased pelvic tilt is likely to compensate for changes in the body mass distribution. The physical activity correlates with the BoS measures and stride length and thus may be important for enhancing gait stability.

Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats.

RATIONALE AND OBJECTIVES: Many studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats. METHODS: The effects of local bilateral microinjections of the selective A2A receptor agonist CGS 21680 or the A2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self-administration on reinstatement of cocaine seeking. RESULTS: The intra-NAc shell, but not intra-infralimbic PFc, administration of CGS 21680 significantly reduced the number of active lever presses and the number of cocaine (0.25 mg/kg) infusions. However, tonic activation of A2A receptors located in the NAc or PFc did not play a role in modulating the rewarding actions of cocaine since neither KW 6002 nor SCH 58261 microinjections altered the cocaine (0.5 mg/kg) infusions. The intra-NAc but not intra-PFc microinjections of CGS 21680 dose- dependently attenuated the reinstatement of active lever presses induced by cocaine (10 mg/kg, i.p.) and the drug-associated combined conditioned stimuli using the subthreshold dose of cocaine (2.5 mg/kg, i.p.). On the other hand, the intra-NAc pretreatment with SCH 58261, but not with KW 6002, given alone evoked reinstatement of cocaine seeking behavior. CONCLUSION: The results strongly support the involvement of accumbal shell A2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking.

Influence of Socioeconomic Factors on Self-Reported Prevalence of Allergic Diseases Among Female University Students.

Until recently, most studies report an increasing prevalence of allergy and asthma. The research suggests that the increase may have to do with changes in lifestyle and living conditions. This study seeks to determine the prevalence and changes in allergic diseases in relation to socioeconomic status (SES) 6 years apart. The research material consisted of data collected in two cross-sectional surveys conducted among university female students in 2009 and 2015 (respectively, 702 and 1305 subjects). The surveys evaluated the incidence of allergic conditions and socio-economic status. The occurrence of allergy was determined on the basis of answers to the questions whether the allergy and specific allergens were defined on the basis of medical work-up. The prevalence of allergic diseases increased from 14.0% to 22.3% over a 6-year period. In both cohorts, allergic diseases were more prevalent among females with high SES than with low SES. In 2009, significant differences were noted in relation to urbanization of the place of living and the number of siblings. In 2015, all socioeconomics factors significantly bore on the prevalence of allergy.

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. METHODS: Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. RESULTS: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. CONCLUSIONS: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133.

Physiological and environmental factors associated with central fat distribution in pubertal girls.

The aim of the work was to determine a degree of explanation of the variation of central fat distribution described by the waist-to-height ratio (WHtR) and waist circumference (WC) by both environmental and biological factors, including hormonal ones. The authors also intended to define the factors which are connected with a risk of abdominal obesity in girls. The study material includes a cross-sectional sample of 297 girls aged 9­16 years, examined in sport and regular schools in Cracow, Poland. Direct anthropometric measurements were done, breast development was assessed (Tanner stage) and leptin and ghrelin concentration in blood serum was estimated (by RIA method). The girls' lifestyles and socio-economic status were investigated through survey questionnaires. The stepwise descending regression method was applied to evaluate a degree of WC, WHtR and BMI variation explanation. A logistic regression analysis was conducted to indicate factors connected with a risk of abdominal obesity (WHtR ³ 0.50) by calculating odds ratio (OR) and 95% confidence interval (CI). Variation of WC and WHtR was explained in, respectively, 53% and 44% by biological factors i.e. age, body height, the Tanner stage and blood serum leptin and ghrelin concentration as well as by environmental factors i.e. obesity prevalence in fathers and the girls' high physical activity. Variation of BMI was explained in 56% by a similar set of variables, excluding the level of physical activity. The biological factors were the highest determinants of an adipose tissue distribution type in the girls. Besides biological factors a significant role was also played by the environmental ones: obesity prevalence in fathers and high level of physical activity. The waist to height ratio seemed to be a more sensitive identifier of environmental behaviours than the general adiposity index.

Prevalence and risk factors of abdominal obesity in Polish rural children.

Secular trends of body mass index (BMI) and waist circumference indicate greater increase in abdominal obesity compared to general obesity. Determinants of obesity described by BMI are relatively well documented in various populations, unlike abdominal obesity described by waist-to-height ratio (WHtR). The aim of the study was to determine prevalence and abdominal obesity (WHtR) risk factors in a cohort of 3048 rural children aged 7-12 years from southern Poland. Biological, socio-demographic and lifestyle factors were analysed, and odds ratio and 95% confidence interval were calculated using a logistic regression analysis. The prevalence of abdominal obesity in rural boys and girls in the sample was 11% and 9% respectively. Obesity in both parents, irregular breakfasts, irregular meals during the day and regularly consumed tea were significant factors of abdominal obesity risks in rural girls. Being the only child, low number of people in a household, obesity in both parents, high energy-dense food index and no exercise significantly increased the risk of abdominal obesity in rural boys. The study demonstrated tendencies similar to other European countries in the prevalence of abdominal obesity among sexes. Lifestyle behaviours should be changed and adapted to each sex since risk factors differ between the sexes and indicate higher eco-sensitivity in boys.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Association of the physical activity with leptin blood serum level, body mass indices and obesity in schoolgirls.

Decreased physical activity is undoubtedly significantly associated with obesity. Similarly, the proper hormones secretion, the proper weight and body development. The aim of this study was to investigate the relationship between body mass composition and leptin concentration in relation to the degree of physical activity expressed in MET-h/week (metabolic equivalent per week). The study included 59 girls, aged 9-16 years (12.55±1.67) and divided into two groups: 1) PA: a physically active group of 29 girls and 2) PI: a group of 30 physically inactive girls. In all, physical activity was assessed using modified questionnaire concerning "activity for adolescents" and expressed in MET-h/week. Serum blood leptin concentrations in fasting girls were determined by RIA. Anthropometric parameters were measured and fatness indices calculated (BMI, SF, WHtR). Body composition (%BF, FM, FFM) was assessed using bioelectrical impedance analysis method (BIA). Statistical analysis showed significant differences between groups of PA and PI concerning values of BMI, WHtR, %BF, WC and MET-h/week as well as in leptin concentrations. In both groups of girls negative correlations between physical activity measured in MET and leptin concentrations and in WHtR were observed. The concentration of leptin was directly proportional to the degree of body fat and to the body composition expressed by BMI, WHtR, log SF, WC and %BF, FM and FFM, respectively. Increased physical activity was associated with lower body fat ratios and WHtR, BMI, WC, %BF, but did not affect significantly the changes in the values of log SF, FM and FFM. Higher values of BMI, WHtR and WC can provide not only a greater risk of obesity in general, but also cause excessive accumulation of fat in the central part of the body (abdominal obesity).

The extent of overweight index in children and adolescents from Cracow, Poland (1971-2000).

Obesity indices describe the percentage of overweight and obese children in a given population but they do not show the extent to which the norms have been exceeded. The aim of this work was to determine the extent of overweight index (EOW), suggested by Jolliffe (2004a,b), by examining children and adolescents from Cracow in order to obtain information on overweight and obesity prevalence and on the amounts by which the BMI age- and sex-specific norms are exceeded, emphasising usefulness of EOW in population studies. The study material comprises three randomly selected groups, representative for Cracow: (1) measured in 1971 which includes 4090 individuals of both sexes and aged 7-19 years, (2) measured in 1983 with 6542 individuals aged 3-19 years and (3) measured in 2000 with 4524 boys and girls aged 3-19 years. The EOW index of overweight is a mean relative deviation from BMI threshold, assuming that for values lower than the threshold ones, the deviation amounts to zero. The EOW index values in boys increased from 0.9 in 1971 up to 2.2 in 2000 i.e. by 144%, indicating an increase of both prevalence of overweight and obesity and an increase of the amount by which the limits of overweight are exceeded. In girls the index also increased, though less dramatically, from 0.7 in 1971 to 1.5 in 2000 i.e. by 114%. An analysis of the results showed that the increasing prevalence of overweight and obesity in children and adolescents is accompanied by an increase of the amount by which the BMI threshold values are exceeded.

Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis.

OBJECTIVE: To examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma. DESIGN: Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone. SETTING: Medline, Embase, and GlaxoWellcome's internal clinical study registers. MAIN OUTCOME MEASURES: FEV(1), morning and evening peak expiratory flow, night awakenings, beta agonist use, and major exacerbations. RESULTS: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 microg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 microg/day and peaked by 500 microg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 microg/day was achieved at doses of 70-170 microg/day and 90% by 100-250 microg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 microg/day. The odds ratio for patients remaining in a study at a dose of 200 microg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV(1 )for an inhaled dose of 200 microg/day against higher doses showed a difference in FEV(1) of 0.13 of a standard deviation (-0.02 to 0.29). CONCLUSIONS: In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 microg, and the maximum effect is achieved with a dose of around 500 microg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 microg/day.

The accuracy of references in Australian and New Zealand Medical Journals.

AIMS: Previous studies have found high error rates in references in biomedical journals. The aim of this paper was to assess the accuracy of references in three Australian and New Zealand general medical journals. METHODS: References from the August 1999 issues of the Medical Journal of Australia, the New Zealand Medical Journal and the Australian and New Zealand Journal of Medicine were assessed for accuracy using PubMed of the National Library of Medicine. RESULTS: This study found a high rate of reference errors in Australian and New Zealand medical journals. The reference error rate ranged from 33.5 to 48.8%. The most frequent errors were in the author's names and in the title. CONCLUSIONS: The reference error rate in Australia and New Zealand medical journals is high and is preventable. Authors should be more diligent and preferably verify cited references against the original article.

Disease demarketing: the college AIDS challenge.

The college population is an important target group for AIDS risk behavior demarketing. While college students appear to be factually knowledgeable they reportedly often engage in high-risk sexual behaviors. This study sheds light on this incongruity by investigating free association images of AIDS and the salient emotions revealed about the disease. The results suggest that students perceive strongly the finality of the disease with fear and sadness representing the most salient emotions. However, men and women may need to be treated as distinct demarketing and promotional targets. Males and females differ in their image of AIDS which may necessitate developing different promotional messages for each of them in order to more effectively influence attitudinal and behavioral change.